一种新型长链非编码 RNA Discn 精细调节复制蛋白 A（RPA）的可用性，以促进基因组稳定性。
A novel lncRNA Discn fine-tunes replication protein A (RPA) availability to promote genomic stability.
机构信息
State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China.
Yunnan Key Laboratory of Animal Reproduction, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China.
出版信息
Nat Commun. 2021 Sep 22;12(1):5572. doi: 10.1038/s41467-021-25827-6.
RPA is a master regulator of DNA metabolism and RPA availability acts as a rate-limiting factor. While numerous studies focused on the post-translational regulations of RPA for its functions, little is known regarding how RPA availability is controlled. Here we identify a novel lncRNA Discn as the guardian of RPA availability in stem cells. Discn is induced upon genotoxic stress and binds to neucleolin (NCL) in the nucleolus. This prevents NCL from translocation into nucleoplasm and avoids undesirable NCL-mediated RPA sequestration. Thus, Discn-NCL-RPA pathway preserves a sufficient RPA pool for DNA replication stress response and repair. Discn loss causes massive genome instability in mouse embryonic stem cells and neural stem/progenigor cells. Mice depleted of Discn display newborn death and brain dysfunctions due to DNA damage accumulation and associated inflammatory reactions. Our findings uncover a key regulator of DNA metabolism and provide new clue to understand the chemoresistance in cancer treatment.
RPA 是 DNA 代谢的主要调节剂，而 RPA 的可用性起着限速因子的作用。尽管许多研究都集中在 RPA 的翻译后调控以研究其功能，但对于 RPA 可用性的控制知之甚少。在这里，我们发现了一种新的长非编码 RNA Discn，它是干细胞中 RPA 可用性的守护者。Discn 在遗传毒性应激下被诱导，并与核仁中的核仁蛋白（NCL）结合。这可以防止 NCL 易位到核质中，并避免不希望的 NCL 介导的 RPA 隔离。因此，Discn-NCL-RPA 途径为 DNA 复制应激反应和修复保留了足够的 RPA 池。Discn 的缺失会导致小鼠胚胎干细胞和神经干细胞/祖细胞中大量的基因组不稳定性。由于 DNA 损伤积累和相关炎症反应，Discn 缺失的小鼠会出现新生儿死亡和大脑功能障碍。我们的发现揭示了 DNA 代谢的关键调节剂，并为理解癌症治疗中的化疗耐药性提供了新的线索。
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